WO2008029217A2 - Inhibiteurs de la dipeptidyl peptidase iv - Google Patents

Inhibiteurs de la dipeptidyl peptidase iv Download PDF

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WO2008029217A2
WO2008029217A2 PCT/IB2007/002403 IB2007002403W WO2008029217A2 WO 2008029217 A2 WO2008029217 A2 WO 2008029217A2 IB 2007002403 W IB2007002403 W IB 2007002403W WO 2008029217 A2 WO2008029217 A2 WO 2008029217A2
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Prior art keywords
amino
phenyl
trifluoroacetic acid
acid salt
oxy
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PCT/IB2007/002403
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English (en)
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WO2008029217A3 (fr
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Surendrakumar Satyanarayan Pandey
Uma Ramachandran
Gajendra Singh
Chithra Santhanagopalan
Venkatachalapathi Sanjay Kadnur
Sivanesan Dharmalingam
Naresh Chidurula
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Orchid Research Laboratories Limited
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Publication of WO2008029217A2 publication Critical patent/WO2008029217A2/fr
Publication of WO2008029217A3 publication Critical patent/WO2008029217A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof.
  • the present invention more particularly provides novel compounds of the general formula (I).
  • the present invention also provides a process for the preparation of the above said novel compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof.
  • the compounds of the present invention are effective in lowering blood glucose, serum insulin, free fatty acids, cholesterol, triglyceride levels and are useful in the treatment and/or prophylaxis of type II diabetes. These compounds are effective in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Surprisingly, these compounds increase the leptin level and have no liver toxicity.
  • the compounds of the present invention are useful for the treatment of disorders associated with insulin resistance such as polycystic ovary syndrome as well as hyperlipidemia, coronary artery disease and peripheral vascular disease; they are also useful in treating an individual at a risk of developing type II diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease, which comprises administration to the individual thereof, repeated doses of an inhibitor of dipeptidyl peptidase IV.
  • the present invention relates to a method for delaying the onset of type II diabetes and alleviating the physiological consequences of type II diabetes.
  • Diabetes is a disease in which the body does not produce or properly use insulin. Around 150 million people have diabetes mellitus worldwide and this number will be double by the year 2025. Much of this increase will occur in developing countries and will be due to population growth, ageing, unhealthy diets, obesity and sedentary lifestyles. By 2025, while most people with diabetes in developed countries will be aged 65 years or more, in developing countries most will be in the 45-64 year age bracket and affected in their most productive years. Diabetes is the leading cause of blindness, lower limb amputations, and renal failure in the United States. The healthcare cost of diabetes is high, with the total estimated cost in the United States exceeding $100 billion. Estimated number of diabetes cases in India in 2002 was 31.7 million. A report by American Diabetes Association, April 2004 stated that by 2030, 79.4 million people are going to be affected by diabetes. As of today, approximately 5% of world population is suffering from type II diabetes.
  • the other targets are the same targets.
  • PDPlB Protein Tyrosine Phosphatase IB
  • Glycogen Synthase Kinase-3 Glycogen Synthase Kinase-3 (GSK-3) Adiponectin
  • GLP-I Insulin Receptor Mimetic Glucagon-like Peptide 1
  • DPPIV Dipeptidylpeptidase IV Inhibitors
  • DPP-IV was discovered in the 1960's as an aminopeptidase. It was identified as characteristic antigen marker CD26 of T cell activation and it was demonstrated that the protein is a component of the T cell receptor complex. Different binding partners were found within this context, for example adenosine deaminase (ADA), tyrosine phosphatase CD45. These compounds act, at least in part, by blocking the inactivation of endogenous incretins such as GLP-I and GIP, resulting in an increased sensitivity to insulin and reduced post-prandial hyperglycaemia. To date, however, these compounds have only been examined as a method for controlling the management of blood glucose levels on an acute basis. The implications of long-term treatment with these compounds have not been considered.
  • the present invention relates to a series of novel compounds that are inhibitors of the enzyme dipeptidyl peptidase IV, to pharmaceutical compositions comprising these inhibitors and their use in the treatment of human diseases.
  • WO 96/38415 discloses, novel 2-amino-3-phenylpropionic acid derivatives represented by general formula (I) or salts,
  • A represents a nitrogenous heterocycle
  • W represents oxygen or carbonyl
  • Rl represents hydroxy, an ester residue or a substituted imide group
  • R2 and R3 represents each hydrogen, alkyl, aralkyl, alkanoyl, benzoyl etc.
  • R4 is hydrogen permuted by benzene ring, a nitro group, an alkoxy group, a halogen atom, or a hydroxyl group.
  • X is , Y is selected from the group consisting of C 1 -S alkylene,
  • Co-8 alkylene ⁇ NR 3 -CO-Co -8 alkylene, C 0- S alkylene-O-Co-s alkylene, Co -8 alkylene- NR 3 ⁇ Co- 8 alkylene and A is selected from the group consisting of
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1-4 alkoxy C 0-6 alkylene, C 1-4 alkoxycarbonyl C 0-6 alkyl, Ci -6 alkylamino C 0-8 alkyl, Ci -6 dialkylamino C 0-8 alkyl, amino C 0-8 alkyl and arylCo -8 alkyl;
  • R 5 is selected from the group consisting of hydrogen, Cj -4 alkoxy Co -6 alkylene, Ci -4 alkoxycarbonyl C 0-6 alkylene;
  • R 6 and R 7 are each independently selected from the group consisting of: hydrogen, C 0-6 alkylamino Co-6 alkyl, Co -6 dialkylamino C 0-6 alkyl.
  • R 1 is a hydrogen atom or an amino-protecting group
  • R 2 is a hydrogen atom or an aryl, aralkyl or alkyl group
  • R is (1) a halogen atom, (2) an aroylamino group, (3) a phenyl group substituted with lower alkyl, phenyl, phenoxy, pyridyl, pyrimidinyl or quinolyl.
  • a naphthyl or tetrahydronaphthyl group optionally substituted with hydroxy, lower alkoxy or (5) an unsaturated mono-cyclic heterocyclic group containing N, O and/or S substituted with lower alkyl, phenyl, naphthyl or tetrahydroquinolyl, in which each substituent on the mono-cyclic heterocyclic group may be further substituted with halogen atom, hydroxy or phenyl, X is a halogen atom, an alkyl group or an alkoxygroup, Y is O or NH, I is 0 or 1, m is 0, 1 or 2 and n is an integer of 0-5.
  • WO 99/29640 comprises the aromatic acids have formula (II),
  • Ar 2 is monocyclic or polycyclic heteroaryl group, which is unsubstituted or substituted with one or more substituents.
  • X 2 is selected from alkylene, sulfonyl, sulfinyl, thio, amino oxy.
  • Ar 3 is 1,4 arylene or heteroarylene and is unsubstituted or substituted with one or more substituents.
  • X 3 is selected from alkylene, alkenylene, carbonylalkynylene and -CH 2 CH(NHR 6 )-, where R 6 is hydrogen, q is 0 or 1 and Y 2 is a carboxylic, sulfonic, boronic or phosphonic acid group.
  • the main objective of the present invention is therefore, to provide novel heterocyclic derivatives and their pharmaceutically acceptable salts that are also useful for the treatment of disorders associated with insulin resistance, such as polycystic ovary syndrome, as well as hyperlipidemia, coronary artery disease and peripheral vascular disease.
  • Another objective of the present invention is to provide novel heterocyclic derivatives and their pharmaceutically acceptable salts having enhanced activities, without toxic effects or with reduced toxic effects.
  • Yet another objective of the present invention is to provide a process for the preparation of novel heterocyclic derivatives of the formula (I) and their pharmaceutically acceptable salts.
  • the present invention relates to novel compounds of the general formula (I),
  • R represents hydrogen, halogen, cyano, substituted or unsubstituted groups selected from linear or branched (Ci-C 4 )alkyl, alkoxy, aryl, aralkyl, heterocyclyl groups, which may be may be mono or fused systems, -NR 10 R 11
  • X represents nitrogen or CH
  • Y represents sulphur, CH 2 , CH-R',
  • R3, R 4 , R 5 , R 6 , R 7 and R 8 may be same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, haloalkyl, alkoxy groups; Rio and Rn may be same or different and
  • the present invention relates to novel compounds of the general formula (I),
  • R represents hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted groups selected from linear or branched (Ci-C 4 )alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like; alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; aryl groups such as phenyl, naphthyl and the like; aralkyl groups such as benzyl, phenylethyl, phenylpropyl and the like; heterocyclyl groups which may be mono or fused systems such as morpholine, piperazine, piperidine, pyrrolidine, thiazolidine
  • R' represents hydrogen, hydroxy and halogen;
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R9, R 10 and R 11 are optionally substituted with one or more substituents selected from nitro, hydroxy, cyano, formyl, azido, alkyl, alkoxy, acyl, halogens, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulf ⁇ nyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, aryl and carboxylic acid or its derivatives.
  • analog includes a compound, which differs from the parent structure by one or more C, N, O or S atoms.
  • a compound in which one of the N atoms in the parent structure is replaced by an S atom is an analog of the former.
  • stereoisomer includes isomers that differ from one another in the way the atoms are arranged in space, but whose chemical formulas and structures are otherwise identical. Stereoisomers include enantiomers and diastereoisomers.
  • tautomers include readily interconvertible isomeric forms of a compound in equilibrium.
  • the enol-keto tautomerism is an example.
  • polymorphs include crystallographically distinct forms of compounds with chemically identical structures.
  • pharmaceutically acceptable solvates includes combinations of solvent molecules with molecules or ions of the solute compound.
  • derivative refers to a compound obtained from a compound according to formula (I), an analog, tautomeric form, stereoisomer, polymorph, hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, by a simple chemical process converting one or more functional groups, such as, by oxidation, hydrogenation, alkylation, esterification, halogenation, and the like.
  • salts of the present invention include alkali metal like Li, Na, and K, alkaline earth metal like Ca and Mg, salts of organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc.
  • Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, trifluoroacetates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Pharmaceutically acceptable salts forming part of this invention include base addition salts such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts.
  • base addition salts such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts.
  • Salts may include acid addition salts which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates, trifluoroacetates, p-toluenesulphonates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • the reaction is carried out at a temperature in the range of room temperature to reflux temperature, mostly 0 0 C to 100 0 C.
  • the single S isomer of the compound of formula (2a) is prepared by condensation of the compound of formula (Ia) (wherein Ri is OH) with halo nitrobenzene followed by alkylation using conventional methods.
  • Hydrogenation of the compound of the formula (3a), (wherein R 3 is NO 2 ) is carried out using a catalyst such as Raney nickel, Pd/C in the presence of solvents such as methanol, ethanol, ethylacetate, n-butylacetate or a mixture thereof.
  • the reaction may be carried out at temperature in the range of 0 0 C to 100 0 C and the duration of the reaction may range from 2 to 24 hours, to produce a compound of the formula (4a).
  • the compound of formula (4a) is reacted with a compound of formula (5a) in the presence of solvents such as toluene, methanol, ethanol, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof or even without solvent.
  • solvents such as toluene, methanol, ethanol, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof or even without solvent.
  • the reaction may be carried out at temperature in the range of 50 °C to 150 0 C and the duration of the reaction may range from 2 to 24 hours, to produce a compound of the formula (6a).
  • the compound of formula (6a) is hydrolyzed by means of base such as alkali hydroxide, alkaline earth metal hydroxide, or by using alkali carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and the like, in the presence of solvents such as water, methanol, ethanol, ethylacetate, n- butylacetate, tetrahydrofuran, 1,4-dioxane or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 0 C to 100 0 C and the duration of the reaction may range from 2 to 24 hours, to produce a compound of the formula (7a).
  • Coupling of the compound of formula (7a) with compound of formula (8a) is carried out under standard peptide coupling conditions, for example, using EDC, HOBt, and a base, generally diisopropylethylamine, in a solvent such as DMF, tetrahydrofuran or methylene chloride for about 3 to about 48 hours at an ambient temperature to provide the compound of formula (9a).
  • the compound of formula (9a) is treated with a dehydrating agent such as
  • deprotection of compound of formula (6a) may be carried out using Pd/C, HCl or trifluoroacetic acid in the presence of solvents such as acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide and the like or mixtures thereof at 0 0 C to 30 0 C.
  • solvents such as acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide and the like or mixtures thereof at 0 0 C to 30 0 C.
  • the deprotection may also be carried out by passing HCl gas in the presence of solvents selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, trifluoroacetic acid, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide and the like or mixtures thereof give the compound of formula (1 Ia).
  • solvents selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, trifluoroacetic acid, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide and the like or mixtures thereof give the compound of formula (1 Ia).
  • solvents selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, trifluoroacetic acid, l-methyl
  • coupling of the compound of formula (7a) with compound of formula (13a) is carried out under standard peptide coupling conditions, for example, using EDC, HOBt, or BOP reagent and a base, generally diisopropylethylamine, in a solvent such as DMF, tetrahydrofuran or methylene chloride for about 3 to 48 hours at an ambient temperature to provide the compound of formula (14a).
  • any reactive group in the substrate molecule may be protected according to the conventional chemical practice.
  • Suitable protecting groups in any of the above-mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the protecting groups P used particularly in the present invention are conventional protecting groups such as t-butoxy carbonyl (t-Boc), trityl, trifluoroacetyl, benzyloxy, benzyloxy carbonyl (Cbz) and the like and deprotection can be done by conventional methods.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 10 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may also be used.
  • a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like
  • solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may also be used.
  • Organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline, guanidine and the like, ammonium or substituted ammonium salts, aluminum salts.
  • Amino acids such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine etc may be used for the preparation of amino acid salts.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, jP-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, oxalic acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, jP-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicy
  • compounds of the invention may contain groups that may exist in tautomeric forms, and though one form is named, described, displayed and/or claimed herein, all the forms are intended to be inherently included in such name, description, display and/or claim.
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form, in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like, wherever applicable or by using chiral bases such as brucine, cinchona alkaloids, their derivatives and the like.
  • Prodrugs of the compounds of formula (I) are also contemplated by this invention.
  • a prodrug is an active or inactive compound that is modified chemically through in-vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • polymorphs of the compounds of the general formula (I), forming part of this invention may be prepared by crystallization of the compounds of formula (I) under different conditions. For example, using different commonly used solvents, or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Heating or melting the compounds followed by cooling gradually or immediately, one can also obtain polymorphs.
  • the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry and powder X-ray diffraction or other such techniques.
  • solvates of the compounds of the formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of the formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane:water, N,N- dimethylformamide:water and the like, preferably water and recrystallization by using different crystallization techniques.
  • solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane:water, N,N- dimethylformamide:water and the like, preferably water and recrystallization by using different crystallization techniques.
  • the present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment of and/or prophylaxis of type II diabetes.
  • These compounds are effective in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • the compositions may be prepared by processes known in the art.
  • the amount of the active ingredient in the composition may be less than 70% by weight.
  • Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, excipients or solvents.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds.
  • the injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • compositions of the invention are effective in lowering blood glucose, serum insulin, free fatty acids, cholesterol, triglyceride levels and are useful in the treatment and/or prophylaxis of type II diabetes. These compounds are effective in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Surprisingly, these compounds increase the leptin level and have no liver toxicity.
  • polycystic ovary syndrome as well as hyperlipidemia, coronary artery disease and peripheral vascular disease; they are also useful in treating an individual at a risk of developing type II diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease, which comprises administration to the individual thereof, repeated doses of an inhibitor of dipeptidyl peptidase IV.
  • the effective dose for treating a particular condition in a patient may be readily determined and adjusted by the physician during treatment to alleviate the symptoms or indications of the condition or disease.
  • a daily dose of active compound in the range of about 0.01 to 1000 mg/kg of body weight is appropriate for administration to obtain effective results.
  • the daily dose may be administered in a single dose or divided into several doses. In some cases, depending upon the individual response, it may be necessary to deviate upwards or downwards from the initially prescribed daily dose.
  • Typical pharmaceutical preparations normally contain from about 0.2 to about 500 mg of active compound of formula I and/or its pharmaceutically active salts or solvates per dose.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents.
  • the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
  • the term "therapeutically effective amount” or “effective amount” refers to that amount of a compound or mixture of compounds of Formula I that is sufficient to effect treatment, as defined below, when administered alone or in combination with other . therapies to a mammal in need of such treatment.
  • animal as used herein is meant to include all mammals, and in particular humans. Such animals are also referred to herein as subjects or patients in need of treatment.
  • the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
  • treatment means any treatment of a disease in a mammal, including: a) Preventing the disease, that is, causing the clinical symptoms of the disease not to develop; b) Inhibiting the disease, that is, slowing or arresting the development of clinical symptoms; and/or c) Relieving the disease, that is, causing the regression of clinical symptoms.
  • Step VII Preparation of (2S)-l- ⁇ (2S)-2-[(*-butoxycarbonyl) amino]-3-[4-(4-(pyridin-2- ylamino) phenoxy) phenyl] propanoyl ⁇ pyrrolidine-2-carbonitrile
  • the DPP IV assay was done using human plasma as a source of DPP IV.
  • the compounds were incubated at a concentration of 1 and 10 ⁇ M in assay buffer containing DPP IV enzyme.
  • the compounds were incubated for 1 hour and then the substrate H-gly-pro AMC was added and further incubated for 20 minutes and then the reaction was stopped on addition of 25% glacial acetic acid.
  • the plates were read in a spectrofluorimeter to get RFU on setting excitation wavelength of 360nm and emission wavelength of 460 nm. Percentage inhibition is calculated as compared to vehicle control. Compounds showing greater than 50% inhibition at 1 ⁇ M were taken for Dose response studies for DPP IV inhibition to calculate IC50 value.
  • Table-I show significant DPP IV inhibition. Table-I

Abstract

La présente invention concerne de nouveaux composés représentés par la formule générale (I), leurs dérivés, analogues, formes tautomères, stéréoisomères, polymorphes, leurs hydrates, solvates, sels pharmaceutiques acceptables, des compositions pharmaceutiques, des métabolites et des promédicaments de ceux-ci. La présente invention concerne plus particulièrement de nouveaux composés représentés par la formule générale (I). Les composés de la présente invention sont efficaces pour abaisser les taux de glucose dans le sang, d'insuline dans le sérum, d'acides gras libres, de cholestérol, les niveaux de triglycérides, et ils sont utiles dans le traitement et/ou la prophylaxie du diabète de type II. Ces composés sont efficaces dans le traitement de l'obésité, des inflammations, de maladies auto-immunes telles que la sclérose en plaques et la polyarthrite rhumatoïde.
PCT/IB2007/002403 2006-08-29 2007-08-22 Inhibiteurs de la dipeptidyl peptidase iv WO2008029217A2 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète

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WO1996018616A1 (fr) * 1994-12-12 1996-06-20 Merck & Co., Inc. 2-aminopyridines substituees utilisees comme inhibiteurs de synthase d'oxyde d'azote
EP0889034A1 (fr) * 1996-03-21 1999-01-07 Banyu Pharmaceutical Co., Ltd. Derives d'aminopyridine

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1996018616A1 (fr) * 1994-12-12 1996-06-20 Merck & Co., Inc. 2-aminopyridines substituees utilisees comme inhibiteurs de synthase d'oxyde d'azote
EP0889034A1 (fr) * 1996-03-21 1999-01-07 Banyu Pharmaceutical Co., Ltd. Derives d'aminopyridine

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète

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